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The search for new peptides to be used as analgesics in place of morphine has been mainly directed to develop peptide analogues or peptidomimetics having higher biological stability and receptor selectivity. Indeed, most of the alkaloid opioid counterindications are due to the scarce stability and the contemporary activation of different receptor types. However, the development of several extremely stable and selective peptide ligands for the different opioid receptors, and the recent discovery of the micro-receptor selective endomorphins, rendered this search less fundamental. In recent years, other opioid peptide properties have been investigated in the search for new pharmacological tools. The utility of a drug depends on its ability to reach appropriate receptors at the target tissue and to remain metabolically stable in order to produce the desired effect. This review deals with the recent investigations on peptide bioavailability, in particular barrier penetration and resistance against enzymatic degradation; with the development of peptides having activity at different receptors; with chimeric peptides, with propeptides, and with non-conventional peptides, lacking basic pharmacophoric features.

Recent evidence highlighted the role of α5β1 integrin in angiogenesis and in regulating αvβ3 integrin function. As a consequence, selective α5β1 integrin inhibitors or dual α5β1/αvβ3 integrin inhibitors are considered promising candidates for the development of cancer therapeutic agents. In this paper, we describe the synthesis and pharmacological characterization of a minilibrary of cyclotetrapeptide mimetics containing a PMRI Arg-Gly-Asp sequence. In particular, c[(R)-βPheψ(NHCO)Aspψ(NHCO)Gly-Arg] (3) displayed a good activity in inhibiting the αvβ3 integrin-mediated cell adhesion of fibronectin or vitronectin, as well as the adhesion of fibronectin to the α5β1 integrin. Interestingly, the diastereomeric compound c[(S)-βPheψ(NHCO)Aspψ(NHCO)Gly-Arg] (2) maintained a good efficacy in inhibiting α5β1 integrin while gaining a certain selectivity over αvβ3 integrin.

In a project dealing with the stereoselective synthesis of dehydro-beta-amino acids, we envisaged the insertion of these unusual amino acids as rigid cores in small constrained molecules mimicking the RGD motif, a peptidic sequence recognized by different integrin subtypes as alpha--beta3 and alpha-5-beta-1. Three different libraries of derivatives have been synthesized in few steps starting from alkylidene acetoacetates. The biological evaluation of the prepared inhibitors confirmed that these unusual beta-amino acids may represent interesting scaffolds for the preparation of novel anticancer agents.

In the course of a program devoted to the synthesis of small peptidic molecules mimicking the RGD (Arg-Gly-Asp) motif, the allylic animation of enantiomeric ally pure carbonates with 4-substituted benzylamines afforded dehydro-p-amino esters through an S(N)2' mechanism. The reaction performed with 4-aminobenzylamine occurred with complete chemoselectivity, as the aliphatic amine was much more reactive than the aromatic one. This allowed useful precursors of biologically active compounds to be obtained, avoiding extra protection-deprotection steps. The same reaction performed on glycine-derived amides gave similar results, allowing a novel type of RGD mimetic to be prepared, whose ability to inhibit cell adhesion was found to be very promising.

Small heterocyclic rings constitute systems of central importance in theoretical, synthetic organic, bio-organic and medicinal chemistry, and in particular aziridines and azirines are very useful and interesting systems as they occur in a number of natural and biologically active substances and as they are useful building blocks and versatile synthetic intermediates. Therefore, the development of efficient and stereoselective methods for synthesis and elaboration of aziridines is an inviting ongoing challenge. Very often, stereogenic centers within such strained heterocycles can be used to direct the stereochemical outcome of subsequent transformations.

Small heterocyclic rings constitute systems of central importance in theoretical, synthetic organic, bioorganic, andmedicinal chemistry, and in particular aziridines and azirines are very useful and interesting systems as they occur in a number of natural and biologically active substances and as they are useful building blocks and versatile synthetic intermediates. Therefore, the development of efficient and stereoselective methods for synthesis and elaboration of aziridines is an inviting ongoing challenge [1]. Very often, stereogenic centers within such strained heterocycles can be used to direct the stereochemical outcome of subsequent transformations.

In recent years, we have been interested in cyclic peptides (CP) as restricted mimics of biologically active, naturally occurring peptides, and in particular, we pursued the synthesis of small, conformationally defined CPs or analogues that mimic - or -turns. Among the different members of the CP family, cyclotetrapeptides (CTP) are considered the smallest system which can reproduce all kinds of turns, but their potential utility is often diminished by difficult synthesis and poor conformational stability. To overcame these limitations, we designed a novel family of CTP analogues, based on a 13-membered partially modified retro-inverso (PMRI) structure, built by introduction of a diamine (a -amino acid mimetic) and a diacid, in different positions. The PMRI-CTPs give rise to a higher degree of chemical and spatial diversity respect to normal CTP, and can be utilized as scaffolds for applications in medicinal chemistry

Small constrained non-peptidic mols. consisting of a polyfunctionalized rigid core, carrying appendages corresponding to arginine and aspartic acid side chains, have been recently reported to be promising for drug development. In this work, the 5,6-dihydropyridin-2-one was envisaged as a scaffold to turn into potential integrin ligands, introducing a carboxylic acid and a basic appendage. The synthesis and the antiadhesion activity of a small library of peptidomimetics capable to recognize alpha-v-beta-3 and alpha-5-beta-1 integrins has been herein reported.

Despite of the recent advances in the structural investigation of complex molecules, the comprehension of the 3D features responsible for the interaction between opioid peptides and micro-opioid receptors still remains an elusive task. This has to be attributed to the intrinsic nature of opioid peptides, which can assume a number of different conformations of similar energy, and to the flexibility of the receptorial cavity, which can modify its inner shape to host different ligands. Due to this inherent mobility of the ligand-receptor system, massive efforts devoted to the definition of a rigid bioactive conformation to be used as a template for the design of new pharmacologically active compounds might be overstressed. The future goal might be the design of peptide or nonpeptide ligands capable of maximizing specific hydrophobic interactions. This review covers the recent opinions emerged on the nature of the ligand-receptor interaction, and the development of suitable models for the determination of the bioactive conformation of peptide ligands active towards micro-opioid receptors.

The synthesis of alpha-benzylamino-beta,gamma-unsaturated acids has been developed starting from a-bromo-a,b-unsaturated chlorides. Via treatment of the acyl chlorides with (R)-pantolactone in the presence of TEA, the in situ formation of the deconjugated ketenes and their direct transformation into chiral esters was performed. The substitution of bromine with benzylamine, followed by acid hydrolysis, allowed to us obtain enantiomerically enriched a-benzylamino-b,c-unsaturated acids.